NZ533712A

NZ533712A - Injection solution comprising an LHRH antagonist

Info

Publication number: NZ533712A
Application number: NZ533712A
Authority: NZ
Inventors: Werner Sarlikiotis; Horst Bauer; Matthias Rischer; Jurgen Engel; Frank Guthlein; Stefano Dominique Di
Original assignee: Zentaris Gmbh
Priority date: 2001-11-26
Filing date: 2002-11-15
Publication date: 2006-01-27
Also published as: HU230992B1; BRPI0214412B8; TW200300352A; DE50209193D1; ES2276970T3; IS7251A; HK1073078A1; TWI312283B; EP1448221A1; RS44904A; CO5580793A2; JP2005510544A; EA010787B1; DE10157628A1; IS2725B; CN100404068C; NO333364B1; PT1448221E; ME00499B; SI1448221T1

Abstract

The following alternative processes for the preparation of aqueous solutions of an LHRH antagonist lead to an increase in the bioavailability, and make possible the lowering of the injection volume to be administered. a) an LHRH antagonist, an organic, physiologically tolerable acid and optionally a surfactant and a bulking agent are dissolved in water for injection, homogenized and processed for injection purposes; or b) an LHRH antagonist and optionally a surfactant and a bulking agent are dissolved using an aqueous saturated solution of an organic, physiologically tolerable acid, homogenizes and processed for injection purposes. The LHRH is disclosed to be selected from teverelix, D-63153, abarelix and azaline B. The solution, which also contains Tween 80 and mannitol, is adjusted to a pH of around 2.5 using an aqueous, saturated gluconic acid delta-lactone solution.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 533712 533712 - 1 - Injection solution comprising an LHRH antagonist Technical field: 5 The invention relates to aqueous injection solutions of an LHRH antagonist using additions of organic, physiologically tolerable acids and/or surfactants and their preparation for prevention of the aggregation of the LHRH antagonist in solution. The injection solutions prepared according to the invention additionally lead to an increase in the bioavailability and make 10 possible the lowering of the injection volume to be administered. Prior art: In controlled ovarian stimulation followed by egg cell removal and 15 techniques of assisted reproduction, besides LHRH agonists (e.g. triptorelin, buserelin), LHRH antagonists (cetrorelix, ganirelix) have especially been used for some time, since they avoid the initial increase in endogenous gonadotropin secretion and immediately lead to a competitive inhibition of gonadotropin-releasing hormone [EP 0 788 799 A2; EP 0 299 20 402 B1]. The LHRH antagonist ganirelix is at present used in a formulation which contains 0.25 mg of ganirelix in 0.5 ml of an aqueous, mannitol-containing solution in the form of a ready-to-use injection (Orgalutran®). The LHRH antagonist cetrorelix (Cetrotide®) is at present supplied in two administration forms: a lyophilizate containing 0.25 mg of cetrorelix 25 combined with a ready-to-use syringe which contains 1 ml of water for reconstitution, and a lyophilizate containing 3 mg of cetrorelix combined with a ready-to-use syringe which contains 3 ml of water for reconstitution. LHRH antagonists, however, are not only used for controlled ovarian stimulation, but can also be used for the therapy of hormone-dependent 30 types of cancer such as, for example, prostate carcinoma. Substances such as abarelix [WO 98/25642] or cetrorelix [WO 00/47234] could be used for this in that the LHRH antagonists could be an alternative to the market-dominating agonists (leuprolide, goserelin) in this therapy. On account of the relatively poor solubility of abarelix in water or physiological media, a 35 depot formulation must be used in order to achieve a long-term action. There are indications, however, that a long-term action could also be caused by good solubility of the LHRH antagonists [G. Jiang, J. Stakewski, R. Galyean, J. Dykert, C. Schteingart, P. Broqua, A. Aebi, M. L. Aubert, INTELLECTUAL PROPERTY OFFICE OF lUZ 1 * OCT 2005 RECEivrn 1" OCT 2005 - 2 - _8 E C EI \/ F p G. Semple, P. Robson, K. Akinsanya, R. Haigh, P. Kiviere, J. rrojnar, J. L. Junien and J. E. Rivier, J. Med. Chem., 2001, 44, 453-467]. Presentation of the invention: 5 It is the object of the invention to prepare an injection solution which achieves a low injection volume together with an increased concentration of the LHRH antagonist by means of its improved solubility or to at least provide a useful alternative. At the same time, the aggregation of the LHRH 10 antagonist in the relatively highly concentrated injection solution should be prevented. It has surprisingly been found that organic, physiologically tolerable acids, particularly carboxylic acids, in particular hydroxycarboxylic acids, but 15 preferably gluconic acid on its own or in combination with surfactants such as, for example, Tween, markedly improve the solubility of LHRH antagonists and thus markedly reduce the proneness to aggregation of these substances. The invention therefore makes it possible to prepare LHRH antagonists in 20 relatively high concentration in aqueous solutions for injection. LHRH antagonists which may be mentioned are, for example, teverelix, D-63153 (Ac-D-Nal-D-pCI-Phe-D-Pal-Ser-N-Me-Tyr-D-Hci-Nle-Arg-Pro-D-Ala-NH2j, abarelix, and azaline B. It was seen that an excess of the respective carboxylic acid must be used; equimolar amounts are not sufficient. 25 Obviously, this effect cannot be explained alone by an in-situ salt formation with basic amino acid residues present such as, for example, arginine, pyridylalanine, lysine. Likewise, the surfactant concentration must not be chosen to be too high, since otherwise the solutions foam too much and aggregation is in turn induced by the surfactants. 30 At the same time, these additions make possible an increase in the bioavailability, since they obviously also slow the spontaneous aggregation in the body after injection or make possible a more rapid absorption of the substance from the site of action. It was seen that the lowered pH of such injection solutions (e.g. pH = 2.5-3) has no influence on the local tolerabiiity 35 of the injection. By increasing the concentration, it is possible to reduce the volume administered, e.g. in the case of cetrorelix from 3 ml to 1 ml for the 3 mg form. It was likewise shown that by means of these additions a good storage stability can be achieved (see Example 1). Although storage for over 6 months at 25°C/60% produced an increase in the impurities, the - 3 - content value in each case was still clearly above 90% (as a rule the lowest value of the use period specification of pharmaceutical products). The turbidity, as a sign of aggregation, increased only slightly. Turbidity values of up to 8 FTU (formazine turbidity unit according to European 5 Pharmacopoeia) are perfectly tolerable. Preservatives such as, for example, phenol or p-chloro-m-cresol do not interfere and can additionally be used for the preservation of the solutions. The use of customary bulking agents, such as mannitol, lactose, glucose and fructose, is likewise possible. 10 Description of a route for carrying out the invention: Example 1 15 500 mg of cetrorelix 2g ofTween80 2.4 g of gluconic acid delta-lactone 95 g of mannitol 20 25 were mixed with water for injection to 2 litres to give a homogeneous solution. The solution was then sterile-filtered and dispensed into ampoules. The ampoules were investigated analytically for purity (HPLC), content (HPLC), pH and aggregation (turbidity) initially and after a storage time of 6 months at 2-8°C and 25°C/60% rel. humidity. Analytical results Starting investigation Investigation after 6 months at 2-8°C Investigation after 6 months at 25°C/60% rel. humidity Purity [%] 0.37 0.69 2.32 Content [%] 100.0 98.7 95.4 PH 3.12 3.16 3.16 Turbidity [FTU] 1.88 2.62 3.92 Example 2 3 0 About 500 mg of D-63153 INTELLECTUAL PROPERTY OFFICE OF N.Z. 19 OCT 2005 received </div>

Claims

<div class="application article clearfix printTableText" id="claims"> - 4 - About 100 mg of Tween 80 About 475 mg of mannitol were adjusted to a pH of about 2.5 using aqueous, saturated gluconic acid delta-lactone solution. A volume of about 50 ml resulted. The mixture was stirred until a clear solution resulted. Analytical results: 10 The turbidity of the solution was initially 2.4 FTU. After 24 h, 2.1 FTU were measured. The purity profile and the content of the solution (HPLC) remained unchanged. Structure of the LHRH antagonist D-63153: 15 Ac-D-Nal-D-pCI-Phe-D-Pal-Ser-N-Me-Tyr-D-Hci-Nle-Arg-Pro-D-Ala-NH2 Example 3 About 100 mg of teverelix 2 0 About 100 mg of Tween 80 About 475 mg of mannitol were adjusted to a pH of about 2.5 using aqueous, saturated gluconic acid delta-lactone solution. A volume of about 10 ml resulted. The mixture was 25 stirred until a clear solution resulted. Analytical results: The turbidity of the solution was initially 6.8 FTU. After 24 h, 8.4 FTU were 30 measured. The purity profile and the content of the solution (HPLC) remained unchanged. Structure of the LHRH antagonist teverelix: 35 Ac-D-Nal-pCI-D-Phe-3-D-Pal-Ser-Tyr-D-H-Cit-Leu-iPr-Lys-Pro-D-Ala-NH2 INTELLECTUAL PROPERTY OFFICE OF N.Z. 13 OCT 2005 received Patent claims 1. Process for the preparation of aqueous injection solutions of an LHRH antagonist, wherein, alternatively -an LHRH antagonist, an organic, physiologically tolerable acid and optionally a surfactant and a bulking agent are dissolved in water for injection, homogenized and processed for injection purposes, or -an LHRH antagonist and optionally a surfactant and a bulking agent are dissolved using an aqueous saturated solution of an organic, physiologically tolerable acid, homogenized and processed for injection purposes. 2. Aqueous injection solution of an LHRH antagonist comprising an LHRH antagonist selected from teverelix, D-63153 (Ac-D-Nal-D-pCI-Phe-D-Pal-Ser-N-Me-Tyr-D-Hci-Nle-Arg-Pro-D-Ala-NH2), abarelix and azaline B and an organic, physiologically tolerable acid wherein said acid is present in greater than an equimolar amount based on the amount of the LHRH antagonist. 3. Aqueous injection solution according to Claim 2, wherein a carboxylic acid is added. 4. Aqueous injection solution according to Claims 2 or 3, wherein a hydroxycarboxylic acid is added. 5. Aqueous injection solution according to any one of Claims 2 to 4, wherein gluconic acid is added. 6. Aqueous injection solution according to any one of Claims 2 to 5, wherein a surfactant is added. 7. Aqueous injection solution according to any one of Claims 2 to 6, which contains Tween as a surfactant. 8. Aqueous injection solution of an LHRH antagonist according to any one of Claims 2 to 7, comprising 500 mg of D-63 153 100 mg of Tween 80 475 mg of mannitol - 6 - adjusted to a pH of around 2.5 in 50 ml using aqueous, saturated gluconic acid delta-lactone solution. 9. Aqueous injection solution of an LHRH antagonist according to any one of Claims 2 to 7, comprising 100 mg of teverelix 100 mg of Tween 80 475 mg of mannitol adjusted to a pH of around 2.5 in 10 ml using aqueous, saturated gluconic acid delta-lactone solution. Aqueous injection solution of an LHRH antagonist, comprising 500 mg of cetrorelix 2.4 g of gluconic acid delta-lactone 2.0 g of Tween 80 95.0 g of mannitol in 2 L of water for injection. 11. Process according to claim 1, substantially as herein described. 12. Aqueous injection solution according to any one of claims 2 to 10, substantially as herein described with reference to any one of the Examples thereof. Aqueous injection solution according to any one of claims 2 to 10, substantially as herein described. INTELLECTUAL PROPERTY OFFICE OF N.Z. i si m 2005 received </div>